CN108774278A - A method of preparing niacinamide nucleosides salt - Google Patents
A method of preparing niacinamide nucleosides salt Download PDFInfo
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- CN108774278A CN108774278A CN201811052696.7A CN201811052696A CN108774278A CN 108774278 A CN108774278 A CN 108774278A CN 201811052696 A CN201811052696 A CN 201811052696A CN 108774278 A CN108774278 A CN 108774278A
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- C—CHEMISTRY; METALLURGY
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/048—Pyridine radicals
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
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Abstract
The present invention relates to a kind of preparation methods of niacinamide nucleosides salt; the niacinamide nucleosides fluoroform sulphonate that triacetyl niacinamide nucleosides fluoroform sulphonate deacetylation obtains replaces ion with acid in organic solvent; crude product is precipitated in crystallization, and mashing obtains corresponding niacinamide nucleosides salt.The displacement ion processes of the present invention overcome the deficiency of chemical method and extraction, are more suitable for industrial production.
Description
Technical field
The invention belongs to nutritional supplement technical fields for this, and in particular to a method of preparing niacinamide nucleosides salt.
Background technology
Niacinamide nucleosides and nicotinamide mononucleotide are the metabolins of nicotinamide adenine dinucleotide, are potential
Natural nutrition supplement.
CN201580040316 is urged using niacinamide and tetra-acetylated ribose as raw material in Trimethylsilyl trifluoromethanesulfonate
Change lower generation triacetyl niacinamide nucleosides fluoroform sulphonate, again with methanol sodium deacetylate obtains niacinamide nucleosides
Fluoroform sulphonate.It is safer chlorion or other anion to replace trifluoromethanesulfonic acid root anion, using four
Hydrogen furans extracts the aqueous solution containing niacinamide nucleosides, sodium chloride and alkali metal fluoroform sulphonate.The ion-exchange process
Ion-exchange-resin process is avoided, but needs to remove water and sodium chloride after extracting, niacinamide nucleosides is degraded in distillation process,
And sodium chloride cannot be removed completely, lab scale total recovery 34%, amplification is reduced to 25% hereinafter, which has limited its industrialized productions.
CN201480043268 is urged using niacinamide and tetra-acetylated ribose as raw material in Trimethylsilyl trifluoromethanesulfonate
Change it is lower generate triacetyl niacinamide nucleosides fluoroform sulphonate, first pyridine ring is restored with remove trifluoromethanesulfonic acid root the moon from
Then son passes through deacetylation, oxidation obtains niacinamide nucleosides.The chemical method deionization avoids ion exchange process, but
It is the increase in oxidation, reduction reaction, step increases, and total recovery is reduced to 20% hereinafter, being also not suitable for industrialized production.
Invention content
The invention reside in the shortcomings of the prior art is solved, a kind of side preparing niacinamide nucleosides salt is provided
Method.The technological difficulties for preparing niacinamide nucleosides salt are to replace in raw material triacetyl niacinamide nucleosides fluoroform sulphonate
Trifluoromethanesulfonic acid radical ion, current research mainly use ion-exchange-resin process, extraction and oxidation-reduction method.The present invention
It is directly exchanged with trifluoromethanesulfonic acid radical ion using anion sour in organic solvent, the niacinamide nucleosides salt crystallization after displacement
It is precipitated, overcomes the deficiency of chemical method and extraction, 70% or more niacinamide nucleosides salt crude yield, total recovery is increased to 50%
More than, it is simple for process, it is more suitable for industrial production.
A kind of preparation method of niacinamide nucleosides salt, includes the following steps：1）With triacetyl niacinamide nucleosides three
Fluorine mesylate is raw material, and niacinamide nucleosides trifluoromethanesulfonic acid salting liquid is obtained by base catalysis deacetylation；
2）Directly niacinamide is precipitated with acid neutralization desalination, displacement ion, crystallization in niacinamide nucleosides trifluoromethanesulfonic acid salting liquid
Nucleosides crude product.
The mixture of the niacinamide nucleosides crude product solvent and acid be beaten to obtain corresponding niacinamide nucleosides salt at
Product.
The niacinamide nucleosides crude product directly synthesizes nicotinamide mononucleotide with phosphorus oxychloride reaction.
In step 1）In：The mixture of triacetyl niacinamide nucleosides fluoroform sulphonate and alcohol is added to containing alkali
Alcoholic solution in, either by the mixture of alkali or alkali and alcohol be added to triacetyl niacinamide nucleosides fluoroform sulphonate and
In the mixture of alcohol.
In step 2）In：Acid is added to niacinamide nucleosides trifluoromethanesulfonic acid salting liquid to neutralize, and salt is filtered to remove after neutralization；
In step 2）In：Acid displacement ion is added in filtrate after the neutralization, small polar solvent crystallization is then added, Buddhist nun gram is precipitated
Amide nucleosides salt crude product.
Alkali in the base catalysis deacetylation is inorganic base or organic base, wherein the inorganic base is hydrogen
Sodium oxide molybdena, lithium hydroxide, potassium hydroxide, ammonium hydroxide, ammonia, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, tertiary fourth
One kind in potassium alcoholate, lithium methoxide, potassium carbonate, sodium carbonate, cesium carbonate, the organic base are tetramethylammonium hydroxide, tetraethyl hydrogen
One kind in amine-oxides, tert-butylamine, methylamine, dimethylamine, ethamine, diethylamine, n-propylamine, isopropylamine, n-butylamine.
The molar ratio of the alkali and triacetyl niacinamide nucleosides fluoroform sulphonate is 0.5:1~20:1, wherein use
The molar ratio of sodium methoxide and triacetyl niacinamide nucleosides fluoroform sulphonate is 1:1~5:1, preferably 1:1~2:1, use ammonia
It is 5 that gas, which is catalyzed with the molar ratio of triacetyl niacinamide nucleosides fluoroform sulphonate,:1~20:1, preferably 5:1~10:1.
Alcohol in the base catalysis deacetylation is one kind in methanol, ethyl alcohol, isopropanol, propyl alcohol, n-butanol,
It is preferred that methanol or ethyl alcohol.
The matter of alcohol and triacetyl niacinamide nucleosides fluoroform sulphonate in the base catalysis deacetylation
Amount is than being 1:1~10:1, preferably 1:1~2:1.
The acid of the neutralization is organic acid or inorganic acid, and the inorganic acid is hydrogen chloride（Or hydrogen chloride methanol solution,
Ethanol solution of hydrogen chloride）, hydrogen bromide（Or hydrogen bromide methanol solution, hydrogen bromide ethanol solution）, hydrogen iodide（Or hydrogen iodide first
Alcoholic solution, hydrogen iodide ethanol solution）, sulfuric acid（Or methanolic solution, ethanol solution of sulfuric acid）In one kind, the organic acid
It is formic acid, acetic acid, trifluoroacetic acid, propionic acid, malonic acid, succinic acid, fumaric acid, maleic acid, citric acid, isocitric acid, ethylenediamine
One kind in tetraacethyl, methanesulfonic acid, p-methyl benzenesulfonic acid, preferably hydrogen chloride（Or hydrogen chloride methanol solution, ethanolic hydrogen chloride are molten
Liquid）Or sulfuric acid（Or methanolic solution, ethanol solution of sulfuric acid）, pH=5~7 after neutralization.
The acid for replacing trifluoromethanesulfonic acid radical ion is organic acid or inorganic acid, and the inorganic acid is hydrogen chloride（Or chlorine
Change hydrogen methanol solution, ethanol solution of hydrogen chloride）, hydrogen bromide（Or hydrogen bromide methanol solution, hydrogen bromide ethanol solution）, hydrogen iodide
（Or hydrogen iodide methanol solution, hydrogen iodide ethanol solution）, sulfuric acid（Or methanolic solution, ethanol solution of sulfuric acid）In one
Kind, the organic acid is formic acid, acetic acid, trifluoroacetic acid, propionic acid, malonic acid, succinic acid, fumaric acid, maleic acid, citric acid, different
One kind in citric acid, ethylenediamine tetra-acetic acid, methanesulfonic acid, p-methyl benzenesulfonic acid can obtain corresponding Buddhist nun gram using different acid
The salt of amide nucleosides is, it is preferable to use hydrogen chloride（Or hydrogen chloride methanol solution, ethanol solution of hydrogen chloride）.
The molar ratio of the acid and triacetyl niacinamide nucleosides fluoroform sulphonate of replacing ion is 1:1~10:1,
It is preferred that 1.5:1~3:1.
The small polar solvent of crystallization is ethyl alcohol, propyl alcohol, isopropanol, n-butanol, ethyl acetate, isopropyl acetate, acetic acid
Butyl ester, methyl acetate, methyl tertiary butyl ether(MTBE), diisopropyl ether, dichloromethane, tetrahydrofuran, acetonitrile, trimethyl phosphate, tricresyl phosphate
Ethyl ester, glycol dimethyl ether, toluene, acetone, ether, the tert-butyl alcohol, 1,2- dichloroethanes, DMF（Dimethylformamide）, in butanone
One kind, ethyl acetate or methyl tertiary butyl ether(MTBE)；Recrystallisation solvent is 1 with reaction dissolvent mass ratio:1~10:1, preferably 2:1
~5:1.
Deacetylation, neutralization, crystallization process temperature be -20~10 DEG C, preferably -10~-5 DEG C.
The solvent of refined (the preparing finished product) of crystallization gained niacinamide nucleosides salt crude product is methanol, ethyl alcohol, isopropyl
The mass ratio of one kind in alcohol, propyl alcohol, n-butanol, preferably methanol, solvent and niacinamide nucleosides salt is 1:1~20:1, preferably
2:1~5:1；And the acid of displacement ion is added, the molar ratio of acid and niacinamide nucleosides salt is 0.1:1~5:1, preferably 0.1:1
~0.5:1；It is -20~35 DEG C to be beaten temperature, preferably -5~5 DEG C.
Niacinamide nucleosides salt crude product is reacted with phosphorus oxychloride, and reaction temperature is -20~10 DEG C, preferably -5~0 DEG C；Three
The molar ratio of chlorethoxyfos and niacinamide nucleosides salt is 1:1~8:1, preferably 2:1~4:1；Reaction dissolvent is trimethyl phosphate, molten
The mass ratio of agent and niacinamide nucleosides salt is 2:1~15:1, preferably 3:1~4:1.
Wherein
Base includes organic base and inorganic base, inorganic base can be sodium hydroxide, lithium hydroxide, potassium hydroxide, ammonium hydroxide, ammonia,
Sodium methoxide, lithium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, have
Machine alkali can be tetramethylammonium hydroxide, tetraethyl ammonium hydroxide, tert-butylamine, methylamine, dimethylamine, ethamine, diethylamine, positive third
One kind in amine, isopropylamine, n-butylamine；
Acid includes inorganic acid and organic acid, and inorganic acid can be hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, and organic acid can be
Formic acid, acetic acid, trifluoroacetic acid, propionic acid, malonic acid, succinic acid, fumaric acid, maleic acid, citric acid, isocitric acid, ethylenediamine tetraacetic
One kind in acetic acid, methanesulfonic acid, p-methyl benzenesulfonic acid；
X=Cl, Br, I, methanesulfonate, p-methyl benzenesulfonic acid root, SO4、HSO4, formate, acetate, trifluoroacetic acid root, propionate,
Malonate, amber acid radical, fumaric acid radical, maleate, citrate, isocitric acid root, ethylenediamine tetra-acetic acid root；
Production technology proposed by the invention, it is easy to operate using displacement trifluoromethanesulfonic acid root anion in organic solvent, no
Using sodium chloride and water, the degradation of niacinamide nucleosides in distillation process is avoided, is very suitable for mass producing.
Triacetyl niacinamide nucleosides fluoroform sulphonate, which reacts under organic base or inorganic base catalysis with alcohol, to be sloughed
Acetyl group is neutralized with inorganic acid or organic acid, and inorganic acid can be passed directly into if gas when neutralization, can also will be inorganic
Acid be dissolved in the solution that methanol is either then added in ethyl alcohol after filtering desalination in solution be added inorganic acid or organic acid replace from
Son, inorganic acid can be passed directly into if gas when replacing ion, can also be dissolved in inorganic acid in methanol or ethyl alcohol again
It is added in solution, adds small polar solvent crystallization, the crude product of niacinamide nucleosides salt is obtained after filtering, 2 are beaten with methanol
Obtain niacinamide nucleosides salt sterling~3 times.It is -20~35 DEG C to be beaten temperature, at preferably -5~5 DEG C, while according to the present invention
Addition proportioning, yield of the invention can be significantly improved, and the present invention is adding by long-term research and Binding experiment etc.
The mol ratio added is not in range disclosed by the invention, or mashing temperature and reaction temperature are not within the scope of the invention, system
Standby effect is poor, and niacinamide nucleosides salt crude product can directly be brought synthesizes nicotinamide mononucleotide with phosphorus oxychloride reaction.
The glycosylation reaction of well known niacinamide and tetra-acetylated ribose must use effective catalyst trifluoromethanesulfonic acid
Front three estersil certainly will introduce trifluoromethanesulfonic acid root anion, existing chemical method, extraction and ion-exchange-resin process in product
Trifluoromethanesulfonic acid root anion can be removed well, but in amplifying production process, also all encounters unvanquishable ask
Topic.The increase of chemical method step, total recovery 20% is hereinafter, aoxidize, there are security risks for reduction reaction；The product that extraction obtains
Containing water and sodium chloride, the degradation of distillation process product is serious, and sodium chloride cannot remove completely；Ion-exchange-resin process is used
A large amount of water dissolution product, freeze-drying operation have limitation.
Specific implementation mode
Embodiment 1-A：The preparation of niacinamide nucleosides chloride
The mixture of triacetyl niacinamide nucleosides fluoroform sulphonate (53g, 0.1mol) and methanol (50ml) is at -10 DEG C
It is added drop-wise in the methanolic ammonia solution (100ml) of 7N, is kept for -10 DEG C and be stirred to react for 24 hours, sample detection after reaction, controls -10
28% hydrogen chloride methanol solution (100ml) DEG C is added dropwise to neutralize, is filtered to remove ammonium chloride, filtrate control -10 DEG C be added dropwise 28% chlorine
Change hydrogen methanol solution (40ml) and replace ion, ethyl acetate (1000ml) is added dropwise and crystallizes, keeps -10 DEG C of stirring 1h, be obtained by filtration
Crude product.
Crude product is added methanol (100ml) and cools to -10 DEG C, and 28% hydrogen chloride methanol solution (6ml) is added dropwise, and is beaten 4h, mistake
Filter obtains once being beaten solid；Primary mashing solid is added methanol (100ml) and cools to -10 DEG C, and 28% methanolic hydrogen chloride is added dropwise
Solution (3ml) is beaten 4h, and mashing temperature is -5 DEG C, and wet product is obtained by filtration, and room temperature in vacuo is dried for 24 hours, and niacinamide nucleosides is obtained
Chloride (15g, 52%).
Embodiment 1-B：The preparation of niacinamide nucleosides chloride
The mixture of triacetyl niacinamide nucleosides fluoroform sulphonate (53g, 0.1mol) and methanol (50ml) is dripped at -7 DEG C
Add in 30% methanol solution of sodium methylate (27g, 0.15mol), kept for -7 DEG C and be stirred to react 1h, sample detection after reaction,
The hydrogen chloride methanol solution (25ml) that -4 DEG C of control is added dropwise 28% neutralizes, filtration from sodium chloride, and filtrate controls -4 DEG C and is added dropwise 28%
Hydrogen chloride methanol solution (25ml) replace ion, be added dropwise ethyl acetate (500ml) crystallize, keep -7 DEG C stirring 1h, filter
To crude product.
Crude product is added methanol (100ml) and cools to -7 DEG C, and 28% hydrogen chloride methanol solution (6ml) is added dropwise, and is beaten 4h, mistake
Filter obtains once being beaten solid；Primary mashing solid is added methanol (100ml) and cools to -7 DEG C, and 28% methanolic hydrogen chloride is added dropwise
Solution (3ml) is beaten 4h, and mashing temperature is -5 DEG C, and wet product is obtained by filtration, and room temperature in vacuo is dried for 24 hours, and niacinamide nucleosides is obtained
Chloride (15g, 52%).
Embodiment 1-C：The preparation of niacinamide nucleosides chloride
The mixture of triacetyl niacinamide nucleosides fluoroform sulphonate (53g, 0.1mol) and methanol (50ml) is dripped at -8 DEG C
It is added in the methanolic ammonia solution (100ml) of 7N, keeps mixed solution at -9 DEG C, be stirred to react for 24 hours, sample detection starting material left 1%
Hereinafter, reaction terminates, the temperature of solution is controlled, and the concentrated sulfuric acid (29g, 0.3mol) neutralization is added dropwise at -7 DEG C, is filtered to remove ammonium sulfate,
The hydrogen chloride methanol solution (40ml) that filtrate controls -8 DEG C of dropwise additions 28% replaces ion, and ethyl acetate (600ml) is added dropwise and crystallizes, protects
- 9 DEG C of stirring 1h are held, crude product is obtained by filtration.
Crude product is added methanol (100ml) solution temperature and cools to -8 DEG C, and 28% hydrogen chloride methanol solution (6ml) is added dropwise, beats
4h is starched, primary mashing solid is obtained by filtration；Primary mashing solid is added methanol (100ml) and cools to -8 DEG C, and 28% chlorination is added dropwise
Hydrogen methanol solution (3ml) is beaten 4h, and wet product is obtained by filtration, and room temperature in vacuo is dried for 24 hours, and mashing temperature is 0 DEG C（It is beaten for the first time
Temperature is identical with second of mashing temperature）, obtain niacinamide nucleosides chloride (16g, 55%).
Embodiment 1-D：The preparation of niacinamide nucleosides chloride
The mixture of triacetyl niacinamide nucleosides fluoroform sulphonate (53g, 0.1mol) and methanol (50ml) -10~-
It is added drop-wise at 7 DEG C in the methanolic ammonia solution (100ml) of 7N, is kept for -10~-7 DEG C and be stirred to react for 24 hours, sample detection reaction terminates
Afterwards, -10~-4 DEG C are controlled, acetic acid (36g, 0.6mol) neutralization is added dropwise, be filtered to remove ammonium acetate, filtrate controls -10~-4 DEG C of drops
Add 28% hydrogen chloride methanol solution (40ml) to replace ion, ethyl acetate (600ml) is added dropwise and crystallizes, keeps -10~-7 DEG C of stirrings
Crude product is obtained by filtration in 1h.
Crude product is added methanol (100ml) and cools to -10~-7 DEG C, and 28% hydrogen chloride methanol solution (6ml) is added dropwise, and is beaten
Primary mashing solid is obtained by filtration in 4h；Primary mashing solid is added methanol (100ml) and cools to -10~-7 DEG C, is added dropwise 28%
Hydrogen chloride methanol solution (3ml) is beaten 4h, and mashing temperature is -20 DEG C, and wet product is obtained by filtration, and room temperature in vacuo is dried for 24 hours, obtained
Niacinamide nucleosides chloride (14.5g, 52%).
Embodiment 1-E：The preparation of niacinamide nucleosides chloride
The mixture of triacetyl niacinamide nucleosides fluoroform sulphonate (53g, 0.1mol) and methanol (50ml) -10~-
It is added drop-wise in the methanolic ammonia solution (100ml) of 7N, is stirred to react for 24 hours when keeping within the scope of -10~-7 DEG C, sample detection at 7 DEG C
After reaction, decompression steams ammonia when controlling within the scope of -2~0 DEG C, and 28% is added dropwise when then controlling within the scope of -10~-4 DEG C
Hydrogen chloride methanol solution (40ml) replaces ion, and ethyl acetate (600ml) is added dropwise and crystallizes, is stirred when keeping within the scope of -10~-7 DEG C
1h is mixed, crude product is obtained by filtration.
When crude product addition methanol (100ml) is cooled within the scope of -10~-7 DEG C, 28% hydrogen chloride methanol solution is added dropwise
(6ml) is beaten 4h, and primary mashing solid is obtained by filtration；Primary mashing solid is added methanol (100ml) and cools to -10~-7 DEG C
When in range, 28% hydrogen chloride methanol solution (3ml) is added dropwise, is beaten 4h, mashing temperature is 35 DEG C, and wet product, room temperature is obtained by filtration
Vacuum drying for 24 hours, obtains niacinamide nucleosides chloride (14.5g, 50%).
Embodiment 2：The preparation of niacinamide nucleosides sulfate：
The mixture of triacetyl niacinamide nucleosides fluoroform sulphonate (53g, 0.1mol) and methanol (50ml) -10~-
In 7 DEG C of methanolic ammonia solutions (100ml) for being added drop-wise to 7N, keep -10~-7 DEG C be stirred to react for 24 hours, sample detection after reaction,
- 2~0 DEG C of decompression of control steams ammonia, then controls -10~-4 DEG C and the concentrated sulfuric acid (20g, 0.4mol) displacement ion is added dropwise, be added dropwise
Ethyl acetate (600ml) crystallizes, and keeps -10~-7 DEG C of stirring 1h, crude product is obtained by filtration.
Crude product is added methanol (100ml) and cools to -10~-7 DEG C, and the concentrated sulfuric acid (2g, 0.02mol) is added dropwise, and is beaten 4h, mistake
Filter obtains once being beaten solid；Primary mashing solid is added methanol (100ml) and cools to -10~-7 DEG C, be added dropwise the concentrated sulfuric acid (2g,
0.02mol), it is beaten 4h, mashing temperature is -20 DEG C, and wet product is obtained by filtration, and room temperature in vacuo is dried for 24 hours, and niacinamide nucleosides is obtained
Sulfate (15g, 50%).
Embodiment 3：The preparation of niacinamide nucleosides bromide：
The mixture of triacetyl niacinamide nucleosides fluoroform sulphonate (53g, 0.1mol) and methanol (50ml) -10~-
It is added drop-wise at 7 DEG C in the methanolic ammonia solution (100ml) of 7N, is kept for -10~-7 DEG C and be stirred to react for 24 hours, sample detection reaction terminates
Afterwards, the hydrogen bromide methanol solution (100ml) for controlling -10~-4 DEG C of dropwise addition 8N neutralizes, and is filtered to remove ammonium bromide, filtrate control -10
The hydrogen bromide methanol solution (40ml) of~-4 DEG C of dropwise addition 8N replaces ion, and ethyl acetate (1000ml) is added dropwise and crystallizes, keeps -10
~-7 DEG C of stirring 1h, are obtained by filtration crude product.
Crude product is added methanol (100ml) and cools to -10~-7 DEG C, and the hydrogen bromide methanol solution (6ml) of 8N is added dropwise, and is beaten
Primary mashing solid is obtained by filtration in 4h；Primary mashing solid is added methanol (100ml) and cools to -10~-7 DEG C, and the bromine of 8N is added dropwise
Change hydrogen methanol solution (3ml), be beaten 4h, wet product is obtained by filtration, room temperature in vacuo is dried for 24 hours, and niacinamide nucleosides bromide is obtained
(17g, 52%)。
Embodiment 4：The preparation of nicotinamide mononucleotide：Triacetyl niacinamide nucleosides fluoroform sulphonate (53g,
30% methanol solution of sodium methylate (27g, 0.15mol) 0.1mol) is added dropwise at -10~-7 DEG C with the mixture of methanol (50ml)
In, kept for -10~-7 DEG C be stirred to react 1h, sample detection after reaction, controls the hydrogen chloride first of -10~-4 DEG C of dropwise additions 28%
Alcoholic solution (25ml) neutralizes, filtration from sodium chloride, and filtrate controls the hydrogen chloride methanol solution of -10~-4 DEG C of dropwise additions 28%
(25ml) replaces ion, and ethyl acetate (500ml) is added dropwise and crystallizes, and keeps -10~-7 DEG C of stirring 1h, filters, is dried under reduced pressure to obtain
Crude product.
The mixture of niacinamide nucleosides crude product (40g, 0.065mol) and trimethyl phosphate (150ml) is at -10~-7 DEG C
When be added dropwise phosphorus oxychloride (40g, 0.26mol), keep -10~-7 DEG C be stirred to react for 24 hours, sample detection after reaction, will be anti-
Answer liquid to pour into ice water (150ml), extracted with dichloromethane (300ml), water layer -10~-0 DEG C in 30% liquid caustic soda and, obtain
The aqueous solution of nicotinamide mononucleotide, with D301 resin desalinations, obtained after freeze-drying solid nicotinamide mononucleotide (10g,
32%)。
Embodiment 5：The preparation of nicotinamide mononucleotide：Triacetyl niacinamide nucleosides fluoroform sulphonate (53g,
0.1mol) it is added dropwise in 30% methanol solution of sodium methylate (21.6g, 0.12mol) at -10 DEG C with the mixture of methanol (38g),
Kept for -10 DEG C be stirred to react 1h, after reaction, the hydrogen chloride methanol solution for controlling -20 DEG C of dropwise additions 28% neutralizes sample detection,
PH=5 after neutralization；Filtration from sodium chloride, the hydrogen chloride methanol solution (13g, 0.1mol) that filtrate controls -10 DEG C of dropwise additions 28% are set
Ion is changed, ethyl acetate (71g) is added dropwise and crystallizes, -10 DEG C of stirring 1h is kept, filters, is dried under reduced pressure to obtain crude product（40g）.
Crude product（40g）Be added methanol (40g) cool to -10 DEG C, be added dropwise 28% hydrogen chloride methanol solution (1.8g,
0.014mol), it is beaten 4h, primary mashing solid is obtained by filtration；Primary mashing solid is added methanol (40g) and cools to -10 DEG C, drop
Add 28% hydrogen chloride methanol solution (0.9g, 0.007mol), is beaten 4h, mashing temperature is -5 DEG C, and wet product, room temperature is obtained by filtration
Vacuum drying for 24 hours, obtains niacinamide nucleosides chloride (15g, 50%).
Niacinamide nucleosides chloride crude product (40g, 0.065mol) and trimethyl phosphate (80g）Mixture at -10 DEG C
When be added dropwise phosphorus oxychloride (10g, 0.065mol), keep -10 DEG C be stirred to react for 24 hours, sample detection after reaction, will react
Liquid pours into ice water (80g）In, with dichloromethane (160g）Extraction, water layer -10 DEG C in 30% liquid caustic soda and, neutralize and arrive ph=3, obtain
To the aqueous solution of nicotinamide mononucleotide, with D301 resin desalinations, obtained after freeze-drying solid nicotinamide mononucleotide (10g,
32%)。
Embodiment 6：The preparation of nicotinamide mononucleotide：Triacetyl niacinamide nucleosides fluoroform sulphonate (53g,
It 0.1mol) is added dropwise in 30% methanol solution of sodium methylate (90g, 0.5mol), protects at -7 DEG C with the mixture of methanol (467g)
It holds -7 DEG C and is stirred to react 1h, after reaction, the hydrogen chloride methanol solution for controlling 10 DEG C of dropwise additions 28% neutralizes sample detection, neutralizes
PH=6 afterwards；Filtration from sodium chloride, filtrate control -4 DEG C be added dropwise 28% hydrogen chloride methanol solution (130g, 1mol) replace from
Son is added dropwise ethyl acetate (5300g) and crystallizes, and keeps -7 DEG C of stirring 1h, filters, is dried under reduced pressure to obtain crude product（40g）.
Crude product (40g) be added methanol (800g) cool to -7 DEG C, be added dropwise 28% hydrogen chloride methanol solution (42g,
0.325mol), it is beaten 4h, primary mashing solid is obtained by filtration；Primary mashing solid is added methanol (800g) and cools to -7 DEG C, drop
Add 28% hydrogen chloride methanol solution (42g, 0.325mol), is beaten 4h, mashing temperature is 5 DEG C, wet product is obtained by filtration, room temperature is true
Sky is dry for 24 hours, obtains niacinamide nucleosides chloride (15g, 50%).
Niacinamide nucleosides chloride crude product (40g, 0.065mol) and trimethyl phosphate (600g）Mixture at -7 DEG C
When be added dropwise phosphorus oxychloride (80g, 0.52mol), keep -7 DEG C be stirred to react for 24 hours, sample detection after reaction, by reaction solution
Pour into ice water (600g）In, with dichloromethane (2400g）Extraction, water layer, in 30% liquid caustic soda and to ph=4, obtain Ni Ke at -0 DEG C
The aqueous solution of amide mononucleotide obtains solid nicotinamide mononucleotide (10g, 32%) with D301 resin desalinations after freeze-drying.
Embodiment 7：The preparation of niacinamide nucleosides bromide：
The mixture of triacetyl niacinamide nucleosides fluoroform sulphonate (53g, 0.1mol) and methanol (26g) is -10~-7
DEG C when be added drop-wise in the methanolic ammonia solution (100ml, 0.7mol) of 7N, keep -10~-7 DEG C be stirred to react for 24 hours, sample detection is anti-
After answering, controlling the hydrogen bromide methanol solution neutralization of -10~-4 DEG C of dropwise addition 8N makes solution ph=5~6, is filtered to remove ammonium bromide,
The hydrogen bromide methanol solution (12.5ml, 0.1mol) that filtrate controls -10~-4 DEG C of dropwise addition 8N replaces ion, and ethyl acetate is added dropwise
(71g) is crystallized, and keeps -10~-7 DEG C of stirring 1h, crude product (45g) is obtained by filtration.
Crude product (45g, 0.065mol) is added methanol (45g) and cools to -10~-7 DEG C, and the hydrogen bromide methanol that 8N is added dropwise is molten
Liquid (1.8ml, 0.014mol) is beaten 4h, and primary mashing solid is obtained by filtration；Primary mashing solid is added methanol (45g) and cools down
To -10~-7 DEG C, the hydrogen bromide methanol solution (0.9ml, 0.007mol) of 8N is added dropwise, is beaten 4h, mashing temperature is -5 DEG C, mistake
Filter obtains wet product, and room temperature in vacuo is dried for 24 hours, and niacinamide nucleosides bromide (20g, 52%) is obtained.
Embodiment 8：The preparation of niacinamide nucleosides bromide：
The mixture of triacetyl niacinamide nucleosides fluoroform sulphonate (53g, 0.1mol) and methanol (430g) -10~-
It is added drop-wise at 7 DEG C in the methanolic ammonia solution (286ml, 2mol) of 7N, is kept for -10~-7 DEG C and be stirred to react for 24 hours, sample detection is anti-
After answering, controlling the hydrogen bromide methanol solution neutralization of -10~-4 DEG C of dropwise addition 8N makes solution ph=5~6, is filtered to remove ammonium bromide,
The hydrogen bromide methanol solution (125ml, 1mol) that filtrate controls -10~-4 DEG C of dropwise addition 8N replaces ion, and ethyl acetate is added dropwise
(5300g) is crystallized, and keeps -10~-7 DEG C of stirring 1h, crude product (45g) is obtained by filtration.
Crude product (45g, 0.065mol) is added methanol (900g) and cools to -10~-7 DEG C, and the hydrogen bromide methanol that 8N is added dropwise is molten
Liquid (41ml, 0.325mol) is beaten 4h, and primary mashing solid is obtained by filtration；Primary mashing solid is added methanol (900g) and cools down
To -10~-7 DEG C, the hydrogen bromide methanol solution (41ml, 0.325mol) of 8N is added dropwise, is beaten 4h, mashing temperature is 5 DEG C, filtering
Wet product is obtained, room temperature in vacuo is dried for 24 hours, and niacinamide nucleosides bromide (20g, 52%) is obtained.
Claims (11)
1. a kind of preparation method of niacinamide nucleosides salt, it is characterised in that：Include the following steps：
1）Using triacetyl niacinamide nucleosides fluoroform sulphonate as raw material, Ni Ke is obtained by base catalysis deacetylation
Amide nucleosides trifluoromethanesulfonic acid salting liquid；
2）Niacinamide nucleosides is precipitated in niacinamide nucleosides trifluoromethanesulfonic acid salting liquid acid neutralization desalination, displacement ion, crystallization
Salt crude product.
2. the preparation method of niacinamide nucleosides salt as described in claim 1, it is characterised in that：The niacinamide nucleosides salt
The mixture of crude product solvent and acid is beaten to obtain corresponding niacinamide nucleosides salt finished product.
3. the preparation method of niacinamide nucleosides salt as claimed in claim 2, it is characterised in that：The niacinamide nucleosides salt
Crude product directly synthesizes nicotinamide mononucleotide with phosphorus oxychloride reaction.
4. the preparation method of niacinamide nucleosides salt as claimed in claim 3, it is characterised in that：The base catalysis deacetylation
Alkali in reaction is inorganic base or organic base, wherein the inorganic base is sodium hydroxide, lithium hydroxide, potassium hydroxide, ammonia
Water, ammonia, sodium methoxide, lithium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, potassium carbonate, sodium carbonate, carbon
One kind in sour caesium, the organic base are tetramethylammonium hydroxide, tetraethyl ammonium hydroxide, tert-butylamine, methylamine, dimethylamine, second
One kind in amine, diethylamine, n-propylamine, isopropylamine, n-butylamine.
5. the preparation method of niacinamide nucleosides salt as claimed in claim 4, it is characterised in that：The alkali and triacetyl Geordie
The molar ratio of gram amide nucleosides fluoroform sulphonate is 0.5:1~20:1, wherein with sodium methoxide catalyzed molar ratio be 1:1~5:
1, preferably 1:1~2:1, it is 5 with ammonia catalysis molar ratio:1~20:1, preferably 5:1~10:1.
6. the preparation method of niacinamide nucleosides salt as claimed in claim 5, it is characterised in that：The base catalysis deacetylation
Alcohol in reaction is one kind in methanol, ethyl alcohol, isopropanol, propyl alcohol, n-butanol, preferably methanol or ethyl alcohol；Alcohol and triacetyl
The mass ratio of base niacinamide nucleosides fluoroform sulphonate is 1:1~10:1, preferably 1:1~2:1.
7. the preparation method of niacinamide nucleosides salt as claimed in claim 6, it is characterised in that：The acid of the neutralization is that have
Machine acid or inorganic acid, the inorganic acid are one kind in hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, the organic acid be formic acid,
Acetic acid, trifluoroacetic acid, propionic acid, malonic acid, succinic acid, fumaric acid, maleic acid, citric acid, isocitric acid, ethylenediamine tetra-acetic acid,
One kind in methanesulfonic acid, p-methyl benzenesulfonic acid, preferably hydrogen chloride or sulfuric acid, pH=5~7 after neutralization.
8. the preparation method of niacinamide nucleosides salt as claimed in claim 7, it is characterised in that：Replace trifluoromethanesulfonic acid root from
The acid of son is organic acid or inorganic acid, and the inorganic acid is one kind in hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, described to have
Machine acid is formic acid, acetic acid, trifluoroacetic acid, propionic acid, malonic acid, succinic acid, fumaric acid, maleic acid, citric acid, isocitric acid, second
One kind in ethylenediamine tetraacetic acid (EDTA), methanesulfonic acid, p-methyl benzenesulfonic acid can obtain corresponding niacinamide nucleosides using different acid
Salt is, it is preferable to use hydrogen chloride.
9. the preparation method of niacinamide nucleosides salt as claimed in claim 8, it is characterised in that：Replace the acid and three of ion
The molar ratio of acetyl group niacinamide nucleosides fluoroform sulphonate is 1:1~10:1, preferably 1.5:1~3:1.
10. the preparation method of niacinamide nucleosides salt as claimed in claim 9, it is characterised in that：The small polarity of crystallization is molten
Agent is ethyl alcohol, propyl alcohol, n-butanol, ethyl acetate, isopropyl acetate, butyl acetate, methyl acetate, methyl tertiary butyl ether(MTBE), two different
Propyl ether, dichloromethane, tetrahydrofuran, acetonitrile, trimethyl phosphate, triethyl phosphate, glycol dimethyl ether, toluene, acetone, second
One kind in ether, the tert-butyl alcohol, 1,2- dichloroethanes, DMF, butanone, isopropanol, ethyl acetate or methyl tertiary butyl ether(MTBE)；Knot
Brilliant solvent dosage is 1-10 times of the volume of reaction dissolvent alcohol, preferably 2-5 times.
11. the preparation method of niacinamide nucleosides salt as claimed in claim 10, it is characterised in that：Crystallization gained niacinamide
The refined solvent of nucleosides salt crude product is one kind in methanol, ethyl alcohol, isopropanol, propyl alcohol, n-butanol, preferably methanol, solvent
Mass ratio with niacinamide nucleosides salt is 1:1~20:1, preferably 2:1~5:1；And the acid of displacement ion is added, acid and Buddhist nun gram
The molar ratio of amide nucleosides salt is 0.1:1~5:1, preferably 0.1:1~0.5:1；It is -20~35 DEG C, preferably -5~5 to be beaten temperature
℃。
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